Cooperation between the thyroid hormone receptor TRalpha1 and the WNT pathway in the induction of intestinal tumorigenesis.

Colorectal tumorigenesis is a multistep process involving the alteration of oncogenes and tumor suppressor genes, leading to the deregulation of molecular pathways that govern intestinal homeostasis. We have previously shown that the thyroid hormone receptor alpha1 (TRalpha1) controls intestinal development and homeostasis through the WNT pathway. More precisely, TRalpha1 directly enhances the transcription of several components of this pathway, allowing increased expression of beta-catenin/Tcf4 target genes and stimulation of cell proliferation. Because the WNT pathway is a major player in controlling intestinal homeostasis, we addressed whether the TRalpha1 receptor has tumor-inducing potential. We generated mice overexpressing TRalpha1 specifically in the intestinal epithelium in a wild-type (vil-TRalpha1) or a WNT-activated (vil-TRalpha1/Apc(+/1638N)) genetic background. The intestine of vil-TRalpha1 mice presents aberrant intestinal mucosal architecture and increased cell proliferation and develops adenoma at a low rate. However, TRalpha1 overexpression is unable to induce cancer development. On the contrary, we observed accelerated tumorigenesis in vil-TRalpha1/Apc(+/1638N) mice compared with the Apc(+/1638N) mutants. Our results suggest that this phenotype is due to cooperation between the activated TRalpha1 and WNT pathways. This is the first report describing the tumor-inducing function of TRalpha1 in the intestine.

Kress E ，Skah S ，Sirakov M ，Nadjar J ，Gadot N ，Scoazec JY ，Samarut J ，Plateroti M ... -  《-》

BCL9-2 promotes early stages of intestinal tumor progression.

The roles of the 2 BCL9 and 2 Pygopus genes in Wnt to β-catenin signaling are not clear in vertebrates. We examined their expression and function in normal and tumor intestinal epithelia in mice and humans. Specific antibodies were generated to characterize the BCL9 and Pygopus proteins in normal intestine and in colon tumors. Targets of BCL9 and Pygopus in colon cancer cells were analyzed using small interfering RNA analysis. Transgenic mice were created that overexpressed BCL9-2 in intestine; these were crossed with APCMin/+ mice to create BCL9-2;APCMin/+ mice. BCL9 and Pygopus2 were expressed in all normal intestinal and colon cancer cells. BCL9-2 was detectable only in the villi, not in the crypts of normal intestine. BCL9-2 was up-regulated in adenomas and in almost all colon tumors, with a concomitant increase of Pygopus2, whereas levels of BCL9 were similar between normal and cancer cells. Transgenic overexpression of BCL9-2 in the intestine of BCL9-2; APCMin/+ mice increased formation of adenomas that progressed to invasive tumors, resulting in reduced survival time. Using small interfering RNA analysis, we found that BCL9s and Pygopus are not targets of Wnt in colon cancer cells, but Wnt signaling correlated with levels of BCL9-2. BCL9-2 regulated expression of β-catenin-dependent and -independent target genes that have been associated with early stages of intestinal tumorigenesis. BCL9-2 promotes early phases of intestinal tumor progression in humans and in transgenic mice. BCL9-2 increases the expression of a subset of canonical Wnt target genes but also regulates genes that are required for early stages of tumor progression.

Brembeck FH ，Wiese M ，Zatula N ，Grigoryan T ，Dai Y ，Fritzmann J ，Birchmeier W ... -  《-》

Transcriptional cooperation between the transforming growth factor-beta and Wnt pathways in mammary and intestinal tumorigenesis.

Labbé E ，Lock L ，Letamendia A ，Gorska AE ，Gryfe R ，Gallinger S ，Moses HL ，Attisano L ... -  《CANCER RESEARCH》

APC and oncogenic KRAS are synergistic in enhancing Wnt signaling in intestinal tumor formation and progression.

Janssen KP ，Alberici P ，Fsihi H ，Gaspar C ，Breukel C ，Franken P ，Rosty C ，Abal M ，El Marjou F ，Smits R ，Louvard D ，Fodde R ，Robine S ... -  《GASTROENTEROLOGY》

The Intestinal Wnt/TCF Signature.

Van der Flier LG ，Sabates-Bellver J ，Oving I ，Haegebarth A ，De Palo M ，Anti M ，Van Gijn ME ，Suijkerbuijk S ，Van de Wetering M ，Marra G ，Clevers H ... -  《GASTROENTEROLOGY》